PubMed · 7024581
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G F Cahill. Fourth annual Jonathan E. Rhoads Lecture.. https://doi.org/10.1177/0148607181005004281
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We investigated the correlation between energy metabolism and neural activity during glucose deprivation and during replacement of glucose with lactate and beta-hydroxybutyrate (OHBA) in neural tissue from rats of different ages. Hippocampal slices were prepared from 4-, 7-, 10-, 13- and 16-day-old and adult rats. The population spikes (PS) were recorded in the pyramidal cell layer of the CA3 area as the index of neural activity. ATP and creatine-phosphate (CrP) levels in each slice were determined during glucose deprivation and during replacement of glucose with lactate or OHBA. After deprivation of glucose, the PS of the slices from 4-, 7- and 10-day-old and adult rats decayed and extinguished in 30 min and the decay time was shortened according to the age of the rat. The levels of ATP and CrP in the slices also decreased, but to a lesser extent than the amplitudes of PS. After substitution of lactate or beta-hydroxybutyrate (OHBA) for glucose, PS of the adult rat disappeared as was the case with glucose deprivation, although the levels of high energy phosphates were well maintained. In the case of the immature rat, however, PS decayed more slowly. Especially in the case of 4-day-old rat, ATP and CrP in the slices were maintained as high as those under the initial concentrations and PS amplitude showed no decay even after 60 min. These results indicate that the presence of glucose is essential for neural activity in the adult rat, and lactate or OHBA cannot replace it for the maintenance of neural activity. In the immature rat, glucose metabolites such as lactate and OHBA are available for both neural activity as well as maintaining the levels of high-energy phosphates in the tissue slice.
Leptin is currently believed to control body composition largely, if not entirely, via hypothalamic receptors that regulate food intake and thermogenesis. Here we demonstrate direct extraneural effects of leptin to deplete fat content of both adipocytes and nonadipocytes to levels far below those of pairfed controls. In cultured pancreatic islets, leptin lowered triglyceride (TG) content by preventing TG formation from free fatty acids (FFA) and by increasing FFA oxidation. In vivo hyperleptinemia, induced in normal rats by adenovirus gene transfer, depleted TG content in liver, skeletal muscle, and pancreas without increasing plasma FFA or ketones, suggesting intracellular oxidation. In islets of obese Zucker Diabetic Fatty rats with leptin receptor mutations, leptin had no effect in vivo or in vitro. The TG content was approximately 20 times normal, and esterification capacity was increased 3- to 4-fold. Thus, in rats with normal leptin receptors but not in Zucker Diabetic Fatty rats, nonadipocytes and adipocytes esterify FFA, store them as TG, and later oxidize them intracellularly via an "indirect pathway" of intracellular fatty acid metabolism controlled by leptin. By maintaining insulin sensitivity and preventing islet lipotoxicity, this activity of leptin may prevent adipogenic diabetes.
1. Mouse ventricular myocytes develop a large transient K+ outward current (I(TO)) which accelerates repolarization and is a crucial determinant for the regulation of the action potential duration at various heart rates. The effect of 3-hydroxybutyrate on I(TO) was investigated under voltage- and current-clamp conditions. 2. The drug blocked I(TO) in a stereoselective manner with the L-enantiomer being the effective and the D-enantiomer, the ineffective form. The blocking action of the L-enantiomer was established immediately and it could be completely washed out within several tens of seconds. 3. The dose-response characteristic for the peak I(TO) showed a strict 1:1 binding of the drug to the receptor with a concentration of half-maximum effect of 2.1 mmol l(-1). 4. The action of L-hydroxybutyrate was voltage independent, did not need channel opening and preferentially affected the slow component of both inactivation and recovery from inactivation. 5. At the high concentration of 20 mmol l(-1) the optically inactive form, the racemate, did not affect I(TO), indicating that the ineffective D-enantiomer interacts with the channels at much lower concentrations. 6. At a concentration of 10 mmol l(-1), L-hydroxybutyrate prolonged the action potential by 218 +/- 26 and 127 +/- 10% (means +/- S.E.M.) at 50 and 90% repolarization, respectively. 7. It is concluded that the non-physiological L-hydroxybutyrate is a novel type of blocker of I(TO), It interacts either with the channel itself, or with a receptor protein closely related to the channel and preferentially affects slow inactivation.